Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).

The Joint Outcome Study Investigators 7Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

The Joint Outcome Study (JOS), a randomized controlled trial, demonstrated that children with severe hemophilia A (HA) initiating prophylactic factor VIII (FVIII) prior to age 2.5 years had reduced joint damage at age 6 years compared with those treated with episodic FVIII for bleeding. The Joint Outcome Continuation Study (JOS-C) evaluated early vs delayed prophylaxis effects on long-term joint health, following JOS participants to age 18 years in an observational, partially retrospective study. Index joint magnetic resonance imaging (MRI) scores of osteochondral (OC) damage (primary outcome), joint physical examination scores, and annualized rates of joint/other bleeding episodes (secondary outcomes) were collected. Thirty-seven of 65 JOS participants enrolled in JOS-C, including 15 randomized to prophylaxis at mean age 1.3 years (“early prophylaxis”); 18 initially randomized to episodic treatment, starting “delayed prophylaxis” at mean age 7.5 years; and 4 with high-titer inhibitors. At JOS-C exit, MRI OC damage was found in 77% of those on delayed and 35% of those on early prophylaxis for an odds ratio of OC damage, in the delayed vs early prophylaxis group, of 6.3 (95% confidence interval, 1.3, 29.9; P = .02). Annualized bleeding rates were higher with delayed prophylaxis (mean plus or minus standard deviation, 10.6 ± 6.6 vs 3.5 ± 2.1; P < .001), including when only comparing time periods on prophylaxis (6.2 ± 5.3 vs 3.3 ± 1.9; P < .05). In severe HA, early initiation of prophylaxis provided continued protection against joint damage throughout childhood compared with delayed initiation, but early prophylaxis was not sufficient to fully prevent damage. This trial was registered at www.clinicaltrials.gov as #NCT01000844.

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Congenital heart failure in the neonate supported by classic imaging findings may allow the implementation of medical therapy for presumed hemangioendothelioma without obtaining a tissue diagnosis. This case report describes a neonate with these classic clinical and radiographic findings but who underwent surgery for failing medical treatment and was diagnosed as having a hepatoblastoma by pathology. This case supports the need to obtain tissue confirmation before beginning medical therapy.